Acute Major Bleeding, Reversal of Coagulopathy
Conditions
Brief summary
The purpose of this study is to evaluate efficacy and safety of a Prothrombin Complex Concentrate (PCC), BE1116. BE1116 will be used for the rapid reversal of coagulopathy induced by vitamin K antagonists in Japanese subjects who require immediate correction of international normalized ratio (INR) due to a major bleed or emergency surgery.
Interventions
BIOLOGICALBE1116 (Prothrombin Complex Concentrate)
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female Japanese subjects greater than or equal to 20 years * Subjects currently on vitamin K antagonist (VKA) therapy * INR greater than or equal to 2 within 3 hours before start of BE1116 infusion * Urgent reversal of VKA therapy for a surgical or invasive medical procedure is required within 24 hours of the start of BE1116 infusion, or presentation with an acute major bleed
Exclusion criteria
* Subjects for whom administration of I.V. vitamin K and VKA withdrawal, alone, can adequately correct the subject's coagulopathy before the infusion of BE1116 * Subjects in whom lowering the INR to within the normal range is not a treatment goal * Use of anticoagulants other than VKAs (or expected use within 1 day) * Medical history for which PCCs are contraindicated * History of thromboembolic event within 3 months of screening * Congenital or acquired abnormality of hemostasis other than receipt of VKAs * Administration of whole blood, plasma, plasma fractions, or platelets within 2 weeks prior to the start of BE1116 infusion * For subjects with intracranial hemorrhage (ICH): * Glasgow Coma Score (GCS) \< 7 * Intracerebral hematoma volume \> 30 cm3 as assessed by computed tomography (CT) scan * For subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm, or acute subdural hematomas (based on neurosurgeon review) * For subarachnoid hemorrhage: any evidence of hydrocephalus, or Hunt and Hess Scale \> 2, or concomitant subdural hematoma * Infratentorial ICH location * Epidural hematomas * Intraventricular rupture of hemorrhage * Requires surgical intervention
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With a Rapid Reversal of VKA Effect | At baseline and at 30 minutes after the end of infusion | A rapid reversal of (Vitamin K antagonist) VKA effect is a reduction of the INR to ≤ 1.3 at 30 minutes after the end of infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed | Baseline CT scan, baseline haematology or the end of infusion, until 24 hours after the end of infusion | Hemostatic efficacy is the binary endpoint of effective or non-effective hemostasis, where 'effective' is a hemostatic efficacy rating of excellent or good, and 'non-effective' is a hemostatic efficacy rating of poor/none. |
| Increase in Plasma Levels of Factor (F)II, FVII, FIX, and FX, and Protein C and Protein S | Before infusion and up to 3 h after the start of infusion | The increase in plasma levels is assessed through response and in vivo recovery (IVR) of FII, FVII, FIX, FX, and protein C and protein S. The incremental IVR \[(IU/dL)/(IU/kg)\] is calculated as follows: (IU/dL activity rise in plasma)/(IU/kg body weight infused) = \[maximum increase in component plasma level within 3 hours compared to pre-infusion (IU/dL)\]/{\[exact dose of component in drug administered (IU)\]/\[body weight (kg)\]}. |
| Percentage of Subjects With INR Correction | From the start of infusion until INR correction, up to 24 hours after the end of infusion | The time taken from the start of infusion to INR correction (defined as an INR ≤ 1.3) is recorded. The percentage of participants with INR correction is calculated. |
| Mean Predicted and Actual Blood Loss (mls) for all Surgical/Invasive Procedures | From the start of surgery/procedure until the end of surgery/procedure | — |
| Percentage of Subjects With INR Correction at Various Times After the End of Infusion | From the end of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the end of infusion | The time taken from the end of infusion to INR correction (defined as an INR ≤ 1.3) is recorded. The percentage of participants with INR correction at 0.5, 1, 3, 6, 12, and 24 h after the end of infusion is calculated. |
| Percentage of Subjects Who Receive Red Blood Cells | From the start of infusion until 24 h after the start of infusion | Red blood cells are packed red blood cells (PRBCs). |
| Percentage of Subjects Who Receive Other Blood Products and Hemostatic Agents | From the start of infusion until 24 h after the start of infusion | Other blood products and hemostatic agents containing coagulation factors (such as whole blood, plasma, albumin, platelets) not including PRBCs. |
| Percentage of Subjects Achieving Hemostatic Efficacy During Surgery | From the start of surgery/procedure until the end of surgery/procedure | Hemostatic efficacy is the binary endpoint of effective or non-effective hemostasis, where 'effective' is a hemostatic efficacy rating of very good or satisfactory, and 'non-effective' is a hemostatic efficacy rating of questionable or none. |
| Overall Treatment-emergent Adverse Events (TEAEs) | From the start of infusion up to the allowed time window of the Day 14 visit for non-serious AEs and from the start of infusion up to the allowed time window of the Day 45 visit for SAEs | Number of participants with TEAEs. TEAEs are defined as adverse events that developed or worsened following exposure to investigational medicinal product. Serious TEAEs are treatment-emergent serious adverse events (SAEs). |
| Mean modified Rankin Scale for all subjects with intracranial haemorrhage | Before infusion and at Day 45 | — |
| Mean Volume (mls) of Wound Drainage for all Surgical/Invasive Procedures | From the start of wound drainage until the end of wound drainage, up to the final safety follow-up visit (Day 45) | — |
| Mean Time (mins) Between Last Suture and Cessation of Wound Drainage for all Surgical/Invasive Procedure | From the time of last suture until the end of wound drainage, up to the final safety follow-up visit (Day 45) | — |
| Vital signs | At baseline and until 24 hours after the end of infusion | Percentage of participants with a clinically significant change in vital signs (including blood pressure, respiratory rate, temperature and pulse rate) |
| Viral serology | At baseline and until Day 45 | Percentage of participants with negative viral serology (for Human immunodeficiency virus, Hepatitis B, Hepatitis A, Hepatitis C and Parvovirus B19) before infusion who become positive after infusion. |
| 45-Day All-cause Mortality | Until Day 45 | — |
Countries
Japan
Outcome results
None listed